Metastatic renal cell carcinoma (RCC) is a devastating disease often refractory to radiation, chemo, and cytokine therapy. Agents targeting the VEGF and mTOR pathways remain the foundation of RCC treatment. Despite marginal improvement in survival with targeted therapy, major limitations exist mainly because of the inter and intra-tumor heterogeneity and redundant pathway activation. While some patients with RCC are inherently refractory to therapy, others who initially respond to single or sequential targeted therapy eventually progress. Efforts to extend the clinical benefit of these agents with combination therapy have resulted in prohibitive toxicity, often with no overall benefit. Targeted multimodality nanoparticles hold great promise in this scenario; however, such modalities for RCC treatment are not currently available. Our goal is to engineer a targeted nanoparticle with clinically validated biomaterials and rationally modified drugs, which will self assemble into a nano-carrier system and provide exquisite spatiotemporal control over drug release to enhance the therapeutic efficacy and reduce off-target toxicity. Our specific aims are the following: Aim 1: Engineer and characterize dual drug-loaded targeted high-efficiency nanoparticles for RCC. Because of the small size and high hydrophobicity, targeted drugs for PI3K and VEGF often exhibit suboptimal pharmacokinetics with a large volume of distribution, and tend to accumulate in healthy tissues causing off target toxicity. Further, traditional pharmaceutical approaches for nano-formulation have been challenge with these molecules because of their incompatible physicochemical properties. We hypothesize that this can be addressed by rationally re-engineering the active agents into pro-drug amphiphiles that facilitate supramolecular nano-assembly into stable high efficiency nanoparticles. We will decorate the SNPs with a targeting ligand for better homing and improved potency. Further, we will optimize conjugation chemistry and ligand density on the SNPs. Aim 2: Pharmacokinetic, bio-distribution and toxicity evaluation of the targeted high-efficiency nanoparticles. In this aim, we will test our hypothesis that targeted SNPs are safe and will preferentially accumulate in tumor tissues yielding high therapeutic index. Aim 3: A mechanistic ananlysis of in vivo efficacy of the high-efficiency nanoparticles in RCC. We hypothesize that mechanistically inspired and surface functionalized nanoparticles that deliver payloads directly to tumor cells and inhibits PI3K-mTORC1/2 and MET/VEGFR2/Tie-2 signaling will regress RCC, evade tumor resistance, and thus improve antitumor outcome with reduced adverse effects. We will test this hypothesis on an array of RCC cell lines and biologically relevant experimental mouse models. We will also perform a head-to-head comparison of targeted vs. untargeted SNPs for their therapeutic efficacy and toxicity. We will dissect the performance of SNPs at the animal (survival, tumor regression), tissue (bio-distribution, toxicity), and molecular (activity of various signaling pathways) levels. We believe that our findings can significantly contribute to the development of novel therapeutic approaches and in the advancement of management strategies in renal cell carcinoma and help reduce associated mortality and morbidity.